The applicant has a funded research program in medical chronoblology, is Associate Director of an NIH funded Harvard-wide Training Program in Sleep, Circadian &Respiratory Neurobiology, and has an excellent track record and commitment to mentoring clinical researchers using where appropriate the formal structure provided by this Training Program. The candidate's goal is to develop a group of outstanding clinical investigators of medical chronoblology - to understand the circadian and sleep/wake mechanisms underlying the day/night pattern in the severity of a number of disorders. The environment for this research is outstanding, with over 60 successful research faculty involved with the Harvard-wide Division of Sleep Medicine. There are 'state of the art'research facilities, comprising intensive physiological monitoring suites in Harvard University's Clinical and Translational Science Center (CTSC) at the Brigham &Women's Hospital site. The candidate has current research funding to determine the role of the body clock versus behaviors on cardiovascular risk markers in healthy young subjects. To understand the clinical relevance of this work, the candidate wishes to extend these studies to examine more vulnerable populations, such as elderly, sedentary, obese and hypertensive individuals. In these groups, epidemiological studies have revealed a high frequency of adverse cardiovascular events around 10 AM. To study such effects, a "Forced Desynchrony" protocol will be used, wherein subjects'behaviors occur at all phases of the circadian cycle. The aims are to determine the effect upon cardiovascular risk markers of the intrinsic circadian rhythm (independent from behaviors) and any interaction between the circadian system and behavioral stressors, including postural changes, exercise and mental stress. Cardiovascular markers of vulnerability include autonomic nervous system measures, cerebral blood flow autoregulation, platelet aggregability and endothelial function. It is anticipated that standard behavioral stressors (standardized changes in posture, activity or sleep/wake state) will have different effects at specific phases of the circadian cycle - revealing vulnerable phases of the circadian system for certain behaviors. The applicant's longer term goals will be to improve therapy in such disorders via modifications in behavior or chronopharmacology. RELEVANCE (See instructions): The severity of many diseases varies across the 24-hour period. For example, heart attacks occur most frequently in the morning a few hours after waking up, and asthma is generally worst at night. We aim to understand the biological basis behind these time-variant changes in disease severity, which could lead to better therapy (e.g. appropriately timed medication to target specific phases of the body clock or to coincide with specific behaviors that cause vulnerability). (End of Abstract)